The invention relates to novel compounds having activity useful for treating conditions which arise or are exacerbated by angiogenesis, pharmaceutical compositions comprising these compounds, a method of treating using said compounds, and a method of inhibiting angiogensis.
Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary however (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a five day period. (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267(16): 10931-10934, and Folkman, J. and Klagsbrun, M., Science, 235: 442-447 (1987)).
Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as xe2x80x9cangiogenic diseasesxe2x80x9d) are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (Folkman, J., Cancer Research, 46: 467-473 (1986), Folkman, J., Journal of the National Cancer Institute, 82: 4-6 (1989)). It has been shown for example that tumors which enlarge to greater than 2 mm, must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner, N., et al., The New England Journal of Medicine, 324(1): 1-8 (1991)).
Although several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases (Gasparini, G. and Harris, A. L., J Clin Oncol 13(3): 765-782, (1995)), there are disadvantages associated with several of these compounds. For example, suramin is a potent angiogenesis inhibitor, but causes (at doses required to reach antitumor activity) severe systemic toxicity in humans. Other compounds, such as retinoids, interferons and antiestrogens are safe for human use but have only a weak anti-angiogenic effect.
In one aspect, the present invention provides a compound the formula of:
A0-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10xe2x80x83xe2x80x83(I)
or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein:
A0 is hydrogen or an acyl group selected from:
(1) Rxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94; wherein n is an integer from 0 to 8 and R is selected from hydroxyl; methyl; N-acetylamino; methoxyl; carboxyl; cyclohexyl optionally containing a one or two double bonds and optionally substituted with one to three hydroxyl groups; and a 5- or 6-membered ring aromatic or nonaromatic ring optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with a moiety selected from alkyl, alkoxy, and halogen; and
(2) R1xe2x80x94CH2CH2xe2x80x94(OCH2CH2O)pxe2x80x94CH2xe2x80x94C(O)xe2x80x94; wherein R1 is selected from hydrogen, alkyl and N-acetylamino, and p is an integer from 1 to 8;
A1 is an amino acyl residue selected from:
(1) alanyl,
(2) asparaginyl,
(3) citrullyl,
(4) glutaminyl,
(5) glutamyl,
(6) N-ethylglycyl,
(7) methionyl,
(8) N-methylalanyl,
(9) prolyl,
(10) pyro-glutamyl,
(11) sarcosyl,
(12) seryl,
(13) threonyl,
(14)xe2x80x94HNxe2x80x94(CH2)qxe2x80x94C(O)xe2x80x94, wherein q is 1 to 8, and
(15)xe2x80x94HNxe2x80x94CH2CH2xe2x80x94(OCH2CH2O)rxe2x80x94CH2xe2x80x94C(O)xe2x80x94, wherein r is 1 to 8;
A2 is an amino acyl residue selected from:
(1) alanyl,
(2) asparaginyl,
(3) aspartyl,
(4) glutaminyl,
(5) glutamyl,
(6) leucyl,
(7) methionyl,
(8) phenylalanyl,
(9) prolyl,
(10) seryl,
(11)xe2x80x94HNxe2x80x94(CH2)qxe2x80x94C(O)xe2x80x94, wherein q is 1 to 8, and
(12)xe2x80x94HNxe2x80x94CH2CH2xe2x80x94(OCH2CH2O)rxe2x80x94CH2xe2x80x94C(O)xe2x80x94, wherein r is 1 to 8;
A3 is an amino acyl residue selected from:
(1) alanyl,
(2) asparaginyl,
(3) citrullyl,
(4) cyclohexylalanyl,
(5) cyclohexylglycyl,
(6) glutaminyl,
(7) glutamyl,
(8) glycyl,
(9) isoleucyl,
(10) leucyl,
(11) methionyl,
(12) norvalyl,
(13) phenylalanyl,
(14) seryl,
(15) t-butylglycyl,
(16) threonyl,
(17) valyl,
(18) penicillaminyl, and
(19) cystyl;
A4 is an amino acyl residue of L or D configuration selected from:
(1) allo-isoleucyl,
(2) glycyl,
(3) isoleucyl,
(4) prolyl,
(5) dehydroleucyl,
(6) D-alanyl,
(7) D-3-(naphth-1-yl)alanyl,
(8) D-3-(naphth-2-yl)alanyl,
(9) D-(3-pyridyl)-alanyl,
(10) D-2-aminobutyryl,
(11) D-allo-isoleucyl,
(12) D-allo-threonyl;
(13) D-allylglycyl,
(14) D-asparaginyl,
(15) D-aspartyl,
(16) D-benzothienyl,
(17) D-3-(4,4xe2x80x2-biphenyl)alanyl,
(18) D-chlorophenylalanyl,
(19) D-3-(3-trifluoromethylphenyl)alanyl,
(20) D-3-(3-cyanophenyl)alanyl,
(21) D-3-(3,4-difluorophenyl)alanyl,
(22) D-citrullyl,
(23) D-cyclohexylalanyl,
(24) D-cyclohexylglycyl,
(25) D-cystyl,
(26) D-cystyl(S-t-butyl),
(27) D-glutaminyl,
(28) D-glutamyl,
(29) D-histidyl,
(30) D-homoisoleucyl,
(31) D-homophenylalanyl,
(32) D-homoseryl,
(33) D-isoleucyl,
(34) D-leucyl,
(35) D-lysyl(Nepsilon-nicotinyl),
(36) D-lysyl,
(37) D-methionyl,
(38) D-neopentylglycyl,
(39) D-norleucyl,
(40) D-norvalyl,
(41) D-ornithyl,
(42) D-penicillaminyl,
(43) D-penicillaminyl(acetamidomethyl),
(44) D-penicillaminyl(S-benzyl),
(45) D-phenylalanyl,
(46) D-3-(4-aminophenyl)alanyl,
(47) D-3-(4-methylphenyl)alanyl,
(48) D-3-(4-nitrophenyl)alanyl,
(49) D-3-(3,4-dimethoxyphenyl)alanyl,
(50) D-3-(3,4,5-trifluorophenyl)alanyl,
(51) D-prolyl,
(52) D-seryl,
(53) D-seryl(O-benzyl),
(54) D-t-butylglycyl,
(55) D-thienylalanyl,
(56) D-threonyl,
(57) D-threonyl(O-benzyl),
(58) D-tryptyl,
(59) D-tyrosyl(O-benzyl),
(60) D-tyrosyl(O-ethyl),
(61) D-tyrosyl, and
(62) D-valyl;
A5 is an amino acyl residue of L or D configuration selected from:
(1) alanyl,
(2) (3-pyridyl)alanyl,
(3) 3-(naphth-1-yl)alanyl,
(4) 3-(naphth-2-yl)alanyl,
(5) allo-threonyl,
(6) allylglycyl,
(7) glutaminyl,
(8) glycyl,
(9) histidyl,
(10) homoseryl,
(11) isoleucyl,
(12) lysyl(N-epsilon-acetyl),
(13) methionyl,
(14) norvalyl,
(15) octylglycyl,
(16) ornithyl,
(17) 3-(4-hydromethylphenyl)alanyl,
(18) prolyl,
(19) seryl,
(20) threonyl,
(21) tryptyl,
(22) tyrosyl,
(23) D-allo-threonyl,
(24) D-homoseryl,
(25) D-seryl,
(26) D-threonyl,
(27) penicillaminyl, and
(28) cystyl;
A6 is an amino acyl residue of L or D configuration selected from:
(1) alanyl,
(2) 3-(naphth-1-yl)alanyl,
(3) 3-(naphth-2-yl)alanyl,
(4) (3-pyridyl)alanyl,
(5) 2-aminobutyryl,
(6) allylglycyl,
(7) arginyl,
(8) asparaginyl,
(9) aspartyl,
(10) citrullyl,
(11) cyclohexylalanyl,
(12) glutaminyl,
(13) glutamyl,
(14) glycyl,
(15) histidyl,
(16) homoalanyl,
(17) homoleucyl,
(18) homoseryl,
(19) isoleucyl,
(20) leucyl,
(21) lysyl(N-epsilon-acetyl),
(22) lysyl(N-epsilon-isopropyl),
(23) methionyl(sulfone),
(24) methionyl(sulfoxide),
(25) methionyl,
(26) norleucyl,
(27) norvalyl,
(28) octylglycyl,
(29) phenylalanyl,
(30) 3-(4-carboxyamidephenyl)alanyl,
(31) propargylglycyl,
(32) seryl,
(33) threonyl,
(34) tryptyl,
(35) tyrosyl,
(36) valyl,
(37) D-3-(naphth-1-yl)alanyl,
(38) D-3-(naphth-2-yl)alanyl,
(39) D-glutaminyl,
(40) D-homoseryl,
(41) D-leucyl,
(42) D-norvalyl,
(43) D-seryl,
(44) penicillaminyl, and
(45) cystyl;
A7 is an amino acyl residue of L or D configuration selected from:
(1) alanyl,
(2) allylglycyl,
(3) aspartyl,
(4) citrullyl,
(5) cyclohexylglycyl,
(6) glutamyl,
(7) glycyl,
(8) homoseryl,
(9) isoleucyl,
(10) allo-isoleucyl,
(11) leucyl,
(12) lysyl(N-epsilon-acetyl),
(13) methionyl,
(14) 3-(naphth-1-y.)alanyl,
(15) 3-(naphth-2-yl)alanyl,
(16) norvalyl,
(17) phenylalanyl,
(1 8) prolyl,
(19) seryl,
(20) t-butylglycyl,
(21) tryptyl,
(22) tyrosyl,
(23) valyl,
(24) D-allo-isoleucyl,
(25) D-isoleucyl,
(26) penicillaminyl, and
(27) cystyl;
A8 is an amino acyl residue selected from:
(1) 2-amino-4-[(2-amino)-pyrimidinyl]butanoyl,
(2) alanyl(3-guanidino),
(3) alanyl[3-pyrrolidinyl(2-N-amidino)],
(4) alanyl[4-piperidinyl(N-amidino)],
(5) arginyl,
(6) arginyl(NGNGxe2x80x2diethyl),
(7) citrullyl,
(8) 3-(cyclohexyl)alanyl(4-Nxe2x80x2-isopropyl),
(9) glycyl[4-piperidinyl(N-amidino)],
(10) histidyl,
(11) homoarginyl,
(12) lysyl,
(13) lysyl(N-epsilon-isopropyl),
(14) lysyl(N-epsilon-nicotinyl),
(15) norarginyl,
(16) ornithyl(N-delta-isopropyl),
(17) ornithyl(N-delta-nicotinyl),
(18) ornithyl[N-delta-(2-imidazolinyl)],
(19) [4-amino(N-isopropyl)methyl)phenyl]alanyl,
(20) 3-(4-guanidinophenyl)alanyl, and
(21) 3-(4-amino-N-isopropylphenyl)alanyl;
A9 is an amino acyl residue of L or D configuration selected from:
(1) 2-amino-butyryl,
(2) 2-amino-isobutyryl,
(3) homoprolyl,
(4) hydroxyprolyl,
(5) isoleucyl,
(6) leucyl,
(7) phenylalanyl,
(8) prolyl,
(9) seryl,
(10) t-butylglycyl,
(11) 1,2,3,4-tetrahydroisoquinoline-3-carbonyl,
(12) threonyl,
(13) valyl,
(14) D-alanyl, and
(15) D-prolyl; and
A10 is a hydroxyl group or an amino acid amide is selected from:
(1) azaglycylamide,
(2) D-alanylamide,
(3) D-alanylethylamide,
(4) glycylamide,
(5) glycylethylamide,
(6) sarcosylamide,
(7) serylamide,
(8) D-serylamide,
(9) a group represented by the formula 
(9) a group represented by the formula xe2x80x94NHxe2x80x94R4;
xe2x80x83wherein:
s is an integer selected from 0 to 8,
R2 is selected from hydrogen, alkyl, and a 5- to 6-membered cycloalkyl ring;
R3 is selected from hydrogen, hydroxy, alkyl, phenyl, alkoxy, and a 5- to 6-membered ring optionally containing from one to two heteroatoms selected from oxygen, nitrogen, and sulfur, provided that s is not zero when R3 is hydroxy or alkoxy; and
R4 is selected from hydrogen, hydroxy, and a 5- to 6-membered cycloalkyl ring.
In another aspect, the present invention provides a composition for treating a patient in need of anti-angiogenesis therapy comprising a peptide defined above in combination with a pharmaceutically acceptable carrier.
Yet another aspect of the present invention provides a method for treating a patient in need of anti-angiogenesis therapy comprising administering to the patient a therapeutically effective amount of a peptide as defined above.
Still yet another aspect of the present invention provides a composition for the treatment of a disease selected from cancer, arthritis, psoriasis, angiogenesis of the eye associated with infection or surgical intervention, macular degeneration and diabetic retinopathy comprising a peptide as defined above in combination with a pharmaceutically acceptable carrier.
In yet another aspect, the present invention provides a method of isolating a receptor from an endothelial cell comprising binding a peptide as defined above to the receptor to form a peptide receptor complex, isolating the peptide receptor complex, and purifying the receptor. In another aspect, the present invention provides a compound of formula (II)
N-Ac-Sar-Gly-AA3-AA4-AA5-AA6-AA7-Arg-Pro-AA10xe2x80x83xe2x80x83(II),
or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof, wherein
AA3 is selected from the group consisting of
(1) glutaminyl,
(2) phenylalanyl,
(3) valyl, and
(4) asparaginyl;
AA4 is selected from the group consisting of
(1) D-isoleucyl,
(2) isoleucyl,
(3) D-leucyl, and
(4) D-alloisoleucyl;
AA5 is selected from the group consisting of
(1) seryl,
(2) methionyl,
(3) allothreonyl,
(4) threonyl, and
(5) tyrosyl;
AA6 is selected from the group consisting of
(1) norvalyl,
(2) seryl,
(3) tryptophyl,
(4) glutaminyl, and
(5) prolyl;
AA7 is selected from the group consisting of
(1) isoleucyl,
(2) D-isoleucyl,
(3) lysyl(acetyl), and
(4) prolyl; and
AA10 is selected from the group consisting of
(1) D-alanylamide,
(2) ethyl amide, and
(3) isopropylamide;
with the proviso that at least one of AA4, AA7, and AA10 is a D-amino acid.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof, and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of treating a patient in need of anti-angiogenesis therapy comprising administering to the patient in need a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof.
In another aspect, the present invention provides a composition for the treatment of a disease selected from cancer, arthritis, psoriasis, angiogenesis of the eye associated with infection or surgical intervention, macular degeneration and diabetic retinopathy comprising a compound of formula (II), or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof, in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of isolating a receptor from an endothelial cell comprising binding a compound of formula (II), or pharmaceutically acceptable salt, ester, prodrug, or solvate thereof, to the receptor to form a peptide receptor complex; isolating the peptide receptor complex; and purifying the receptor.